A Phase I/II, Open Label, Multicentre, Ascending Single Dose, Safety Study of a Novel Adeno- Associated Viral Vector (FLT180a) in Patients With Haemophilia B
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 入组人数
- 10
- 试验地点
- 12
- 主要终点
- Frequency and Severity of Treatment-emergent Adverse Events (TEAEs) (Safety)
研究概览
简要总结
Severe haemophilia B (HB) is a bleeding disorder where a protein made by the body to help make blood clot is either partly or completely missing. This protein is called a clotting factor; with severe haemophilia B, levels of clotting factor IX (FIX) (nine) are very low and affected individuals can suffer life threatening bleeding episodes. HB mainly affects boys and men (normally one in every 30,000 males). Current treatment for HB involves intravenous infusions of factor IX as regular treatment (Prophylaxis) or 'on demand'. On demand treatment is highly effective at stopping bleeding but cannot fully reverse long-term damage that follows after a bleed. Regular treatment can prevent bleeding, however can be invasive for patients and also expensive. This research study aims to test the safety and effectiveness of a gene therapy which produces Factor IX protein in the body. The gene will be given using an inactivated virus called "the vector" ( FLT180a), in a single infusion. The vector has been developed from a virus known as an adeno- associated virus, that has been changed so that it is unable to cause a viral infection in humans. This "inactivated" virus is further altered to carry the Factor IX gene and to make its way within liver cells where Factor IX protein is normally made.
Up to three different doses cohorts of FLT180a will be tested, in up to 24 patients with severe haemophilia B. Patients will be recruited from haemophilia centres in the EU and US. Patients will be in the trial for approximately 40 weeks and will undergo procedures including physical examinations, bloods tests, ECGs and liver ultrasounds.
详细描述
This was a Phase I/II, open-label, multicentre, ascending single-dose, safety study of FLT180a in patients with severe (FIX activity <1%) or moderately severe (FIX activity 1% to 2% with severe bleeding phenotype) HB. Up to 24 patients were planned to be enrolled; however, the study was terminated early (on 20 October 2020) after 10 patients had been enrolled because of changes to the clinical development plan and recruitment difficulties due to the COVID-19 pandemic.
Patients who provided consent to participate and had historical data on bleeding and FIX consumption documented from the previous 3 years' medical notes were screened for eligibility in this study. During the screening period, patients completed a diary to prospectively record ongoing bleeding events and FIX consumption. Patients were monitored through a comprehensive schedule of safety assessments at outpatient visits for 26 weeks.
On completion of the study, patients are to be followed for 15 years under a separate long term follow-up protocol.
Patients who provided consent to participate in this study underwent screening assessments up to 52 weeks before study Day 0 (FLT180a infusion). Due to the risk of bleeding in this patient population, a washout from the patient's FIX concentrate regimen was not mandated. The investigator was to demonstrate, from the patient's medical records, a documented FIX activity level of <1% for severe patients or <2% for moderately severe patients. If (at the investigator's discretion) a FIX concentrate washout was undertaken during the screening period, a minimum of 5 days' washout was required.
Treatment-eligible patients reported to the study site on the day before receiving the gene therapy infusion (Day 1). On Day 0, FLT180a was administered as a single dose, slow intravenous (IV) infusion into a peripheral vein. The patient remained in the study centre for ≥12 hours and until the investigator deemed the patient fit to be discharged. The first 2 patients treated at each dose level remained at the study centre for 24 hours after infusion before discharge.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- Male
- 接受健康志愿者
- 否
入选标准
- •Adults males, ≥ 18 years of age.
- •Confirmed diagnosis of HB defined as one of the following:
- •Documented severe FIX deficiency with plasma FIX activity of <1% of normal, or
- •moderately severe FIX deficiency with plasma FIX activity level between ≥1% and ≤2% and a severe bleeding phenotype defined by one of the following: i. On prophylaxis for a history of bleeding, or ii. On demand therapy with a history of 4 or more bleeding episodes/year on average over the past 3 years, or iii. evidence of chronic haemophilic arthropathy (pain, joint destruction, and loss of range of motion).
- •Able to give full informed consent and able to comply with all requirements of the trial including 15-year long-term follow-up.
- •Willing to practice barrier contraception until at least 3 consecutive semen samples after vector administration are negative for vector sequences.
- •Lack of neutralising anti-AAV-S3 antibodies using an in vivo transduction inhibition assay within 4 weeks of vector administration.
- •At least 150 exposure days to FIX concentrates.
排除标准
- •Presence of neutralising anti-human FIX antibodies (inhibitor, determined by the Bethesda inhibitor assay) at the time of enrolment or a previous history of FIX inhibitor;
- •Patients at high risk of thromboembolic events (high risk patients would include those with a history of arterial or venous thromboembolism (e.g. deep vein thrombosis, pulmonary embolism, non-haemorrhagic stroke, arterial embolus) and those with acquired thrombophilia including conditions such as atrial fibrilation);
- •Use of investigational therapy for haemophilia within 30 days before enrolment;
- •Patients with active hepatitis B or C, and hepatitis B surface antigen (HBsAg) or hepatitis C virus (HCV) Ribonucleic acid (RNA) viral load positivity, respectively, or currently on antiviral therapy for hepatitis B or C. Negative viral assays in 2 samples, collected at least 6 months apart, will be required to be considered negative. Both natural clearers and those who have cleared HCV on antiviral therapy are eligible.;
- •Serological evidence of human immunodeficiency virus (HIV-1);
- •Evidence of liver dysfunction (persistently elevated alanine aminotransaminase, aspartate aminotransferase, bilirubin >1.5 x upper limit of normal);
- •Platelet count <50 x 109/L;
- •Uncontrolled glaucoma, diabetes mellitus, or hypertension;
- •Malignancy requiring treatment;
- •Patients with uncontrolled cardiac failure, unstable angina or myocardial infarction in the past 6 months;
- •Poor performance status (World Health Organization score >1);
- •Prior treatment with any gene transfer medicinal product;
- •Known or suspected intolerance, hypersensitivity or contraindication to the investigational product and non-investigational medicinal products or their excipients;
- •Planned major elective surgery prior to the end of trial.
- •Current or relevant history of a physical or psychiatric illness or any medical condition that in the opinion of the investigator could affect the patients safety or interfere with the study assessments.
- •Cytomegalovirus (CMV) Immunoglobulin G (IgG) positive patients who are CMV PCR positive at screening.
结局指标
主要结局
Frequency and Severity of Treatment-emergent Adverse Events (TEAEs) (Safety)
时间窗: From Day 0 (first dose of FLT180a) until week 26 post infusion (up to 26 weeks)
Safety as assessed by the reporting of AEs according to Common Terminology Criteria for Adverse Events (CTCAE) v5.0
Number of Participants With FIX Activity Response
时间窗: From screening until week 26 post infusion (Up to 38 weeks)
The proportion of participants at the terminal dose (1.3 x 10e\^12 vg/kg) achieving clinical FIX response and proportion of patients achieving normalised FIX response at Week 26. A clinical FIX response is defined as achieving a FIX activity of 5% to 150%. Normalised FIX response is defined as achieving FIX activity in the normal range (50-150%).
次要结局
- Number of Participants With a Change From Baseline or Abnormal Finding From Routine Safety Assessments(From screening until week 26 post infusion (Up to 38 weeks))
- Viral Shedding Evaluated as Time to Unquantifiable Vector Genomes(From screening until time to unquantifiable results of vector genomes in all matrices, up to an average of 5.14 weeks)
- Change From Baseline in FIX Activity as a Percentage of Normal Values(Week 26/EOS)
- Endogenous FIX Production(From screening until week 26 post infusion)
- FIX Concentrate Usage(Baseline and Post Dose (Day15 post infusion to Week26/End of Study))
- Immune Response - Development of Inhibitors(Week 1, week 2, week 3, week 6, week 9, week 12, week 16, week 20 and week 26/EOS post infusion)
- Bleeding Frequency(Baseline and Post-Dose (Day 15 to Week 26/EOS))